6-methyl-9alpha fluoro-11 oxygenated pregnenes



llnited States Patent 6-METHYL-9m rLUoRo-u OXYGENATED PREGNEN ES The present invention relates to steroid compounds and is concerned with 6-hydrocarbyl substituted steroid compounds, particularly with 6-methyl-9a-fiuoro-l15,17a-dihydroxy-4-pregnene-3,20-dione, the 21-iodo substituted intermediate, 6-methyl-9a-fluoro-l7a-hydroxy-4-pregnene-3, 11,20-t1 'i 0ne, and a process for the production therefor.

This application is a continuation-in-part of applications S. N. 608,661, filed September 10, 1956 and now abandoned, and S. N. 623,790, filed November 23, 1956.

The new compounds and the process of the present invention are illustratively represented by the following formulae:

CH3 CH3 CHQOH CHzOSOzR 0=0 =0 '---on '----on g IF 3 I OH; II

OHQI

Hz III 7 wherein R is an organic radical such as methyl, ethyl,

ing 6-rnethyl-9a-fiuoro-l1 3,170:,21-trihydroxy-4-pregneneice 115,17ot,21-trihydroxy-4-pregnene-3,20-dione with sodium iodide in acetone solutionto obtain 6-methyl-9u-fluor0- 1113,17u-dihydroXy-21-iodo-4-pregnene-3,20-dione (III) treating the thus obtained 6-methyl-9a-fluoro-115,174 dihydroxy-21-iodo-4-pregnene-3,20-dione with a reducing agent such as sodium-thiosulfate, sodium bisulfite, potassium bisulfite, or the like, in an aqueous organic solvent mixture to obtain 6-methyl-9a-fiuoro41 8,17u-dihydroXy- 4-pregnene-3,20-di0ne (IV) and if desired oxidizing the thus obtained 6-methyl-9a-fluoro-11fl,17wdihydroxy-4- pregnene-3,20-dione with chromic anhydride, N-bromoacetamide, N-bromosuccinimide, or the like, to give 6- methyl 9a fluoro 17a hydroxy-4-pregnene-3,l1,20- trione (V).

It is an object of the instant invention to provide 6- methyl c fluoro 115,170: dihydroxy 4 pregnene- 3,20-dione and 6 methyl 90c fluoro-17a-hydroxy-4- pregnene-3,ll,20-trione and, in particular, the 6a-epimers, 6a methyl 90c fluoro 11fi,17u dihydroxy-4-pregnene- 3,20-dione and 60 methyl 9a flu0ro-17u-hydroxy-4- pregnene-3,11,20-trione. It is another object of the instant invention to provide a process for the preparation of 6- methyl-9a fluoro 113,17a dihydroxy 4 pregnene-3, 20-dione and 6-methyl-9m-fluoro-17a-hydroxy-4-pregnene- 3,11,20-trione and the 21-iodo analogues thereof, especially 6 methyl 9a fluoro 115,170: dihydroxy 21 iodo- 4-pregnene-3,20-dione. Other objects of this invention will be apparent to those skilled in the ein to which this invention pertains.

The novel 60: methyl 90c fluoro 115,17a-dihydroxy- 4-pregnene-3,20-diones, the 60: methyl 9a fluoro 17ahydroxy-4-pregnene-3,11,20-triones possess a highorder of physiological activity, and possess activity spectra different from the adrenocortical hormones found in nature such as hydrocortisone and cortisone especially in their effect on mineral and water metabolism. These compounds cause a loss of salt and water which makes them especially valuable in the management of chronic congestive heart failure and in the treatment of cirrhosis of the liver, the nephrotic syndrome and the treatment of eclampsia and preeclampsia. The novel synthetic corticosteroid hormones of the present invention possessalso anti-inflammatory, glucocorticoid, uterine, ovarial and adrenal growth-depressional, and adrenocorticoid activity. The anti-inflammatory activity is especially noticeable in all the steroids of the present invention. The 6fl-epimers, 6 5 methyl 9a fluoro 11,3,17u-dihydroxy-4-pregnene- 3,20-dioneand 6B methyl 90c fluoro 17a hydroxy-4- pregnene-3,ll,20-trione have the same type of activity-as the 6a-epimers.

The novel 6 methyl 9a-fluoro11B,17a-dihydroxy-4- pregnene 3,20 diones and 6 methyl 9a fluoro 17ahydroxy-4-pregnene 3,11,20 trione are useful in oral, parenteral and topical compositions. In oral compositions the material may be given as tablets illustratively using either polyethylene glycol 4000 or 6000 as a carrierv or lactose and/ or sucrose as a diluent. 'The novel 6umethyl- 9oc fluoro 11,13,170; dihydroxy 4 pregnene 3,20- dione and 60a methyl 90c fluoro 17a hydroxy 4 pregnene-3,11,20-trione are useful for topical application as ointments, lotions, jellies, creams, suppositories, bougies, aqueous suspensions etc. Examples of advantageous topical'compositions are given below. While the examples below are to the 6et-methyl-9a-fluoro-11fl,17a-dihydroxy- 4 pregnene-3, 20-dione and 6a methyl 9u.- fluoro 170chydroxy 4 pregnene-3,11,20 trione, equivalent amounts of 65 methyl 90c fluoro 11fi,17oc dihydroxy 4- pregnene-3,20-d ione and 6,8 methyl 9m fluoro 170chydroxy 4 pregnene 3,11,20 trione and of other 6 lower-alkyl and phenyl homologues of the compounds of this invention are substitutable therein.

A dermatological and ophthalmic ointment for the human or animal organism has the following composition:

Lbs.

Wool fat USP 100 Mineral oil USP 125 6a methyl 9oz fluoro 115,170: dihydroxy- 4- pregnene 3,20 dione (micronized) 1.0

Whlte petrolatum USP 500 Incorporation of an antibiotic in the above ointment, especially neomycin sulfate, has therapeutic advantages each active ingredient potentiating and supplementing the useful properties of the other. Such an ointment is as In place of, or in addition to neomycin sulfate, other antlblotics such as bacitracin, circulin, polymyxin B sulfate, gramicidin, streptomycin sulfate, dihydrostreptomycin sulfate, oxytetracycline, chlorotetracycline, tetracycline, chloramphenicol and the sulfonamides can be used in conjunction with the steroids of the present lnvention for preparations such as the above ointments.

The 6 methyl 9a fluoro 11,8,17u dihydroxy 21- iodo-4-pregnene-3,ZO-dione is useful as an intermediate in the production of 6-methyl-9u-fluoro-11 3,17u-dihydroxy-4-pregnene-3,20-dione as shown in Example 3.

In carrying out the process of the instant invention, 9afiuoroe6-methylhydrocortisone (6a-methyl-9a-fluoro-11B,- 179:,21 trihydroxy 4 pregnene-3,20-dione or 6 8- methyl 90c fluoro 11 8,17a,21' trihydroxy 4 pregnene 3,20 dione) is treated with an acid halide of a sulfonic acid such as methanesulfonic acid, ethanesulfonic ac d, propanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, uor fi-naphthanesulfonic acid, or the like, with methanesulfonic' acid halides especially methanesulfonyl chloride preferred. The steroid is in the preferred embodiment of the instant invention reacted with the alkylor arylsulfonyl halide, in solution such as 1n a solvent, for example, pyridine, benzene, toluene, or the like, at a temperature between minus ten and plus thirty degrees centigrade, providing that at the lower temperature the reaction mixture has not solidified. Pyridine as solvent and a temperature between minus ten and plus ten degrees centigrade is preferred. The time 'of reaction is usually between thirty minutes and six or eight hours, after which the product, 6-methy1-9a-fiuoro- 11[3,17o:,21 trihydroxy 4 pregnene 3,20 dione 21- 'alkylor arylsulfonate is removed in conventional manner,"for example, by evaporating the solvent until a dry residue is obtained or by extracting the material from an aqueous solution. For extraction, solvents such as methylene chloride, chloroform, carbon tetrachloride, benzene, ether, toluene, or the like may be used. Re-

moving the extraction solvent by distillation leaves the crude" 6 methyl 95: fluoro 11}3 ,17a,21 trihydroxy- 4-pregnene-3,20-dione 21-alkylor arylsulfonate.

For the purpose of producing the final product, it is unnecessary to purify the thus obtained 21-arylor 21- 'alkylsulfonate, and the crude steroid sulfonate ester is used for the production of 6-methyl-9wfiuoro-l118,17qdihydroxy-21-iodo-4-pregnene-3,20-dione.

The 21-iodo compound ..is prepared .by reacting .the alkylor arysulfonate of ,6-methyl-9a-fluoro-11fi,17a,21- trihydroxy-4-pregnene-3,20-dione with sodium or potassium iodide in acetone solution. A molar excess of sodium iodide (three to twenty moles of sodium iodide per mole of steroid) is generally preferred for this reaction and the reaction mixture containing 6methyl-9afluoro 1lB,17a,2l trihydroxy 4 pregnene 3,20- dione 21-alkylor arylsulfonate and sodium iodide in acetone is heated to reflux for a period of three or four minutes to half an hour. The thus produced 6-methylc fluoro 11/3,17 x dihydroxy 21 iodo 4 pregnene-3,20-dione is isolated by evaporating the solvent. For the subsequent reaction it is unnecessary to purify the thus obtained 6-methyl-9a-fluoro-11fi,17a-dihydroxy- 21-iodo-4-pregnene-3,20-dione.

In order to obtain 6-methyl-9u-fluoro-1,l;3,17a-dihydroxy-4-pregnene-3,ZO-dione, the crude 6-methyl-9 fluoro 115,170: dihydroxy 21 iodo 4 pregnene- 3,20-dione is reacted with a reducingagent such assodium or potassium thiosulfate, sodium bisulfite, or the like. In the preferred embodiment of the invention, the crude 6 methyl 9a fluoro 11,6,170: dihydroxy-21-iodo-4- pregnene-3,20-dione is slurried with zinc and acetic acid and the mixture stirred at room temperature for a period of five minutes to two hours. The product is isolated from the aqueous reaction mixture by conventional methods such as filtration or extraction with a water-immiscible organic solvent, such as ether, benzene, methylene chloride, ethylene chloride, carbon tetrachloride, chloroform, hexane, heptane, or the like, and evaporating the extracts. Purification of the thus obtained 6-methyl- 9a fluoro 116,170 dihydroxy 4 pregnene 3,20- dione is carried out by conventional means such as recrystallization from ether, acetone, methanol, ethanol, Skellysolve B hexane, mixtures thereof, or the like; or by chromatography.

The oxidation of 6-methyl-9u-fluoro-1113,17a-dihydroxy-4 pregnene-3,2 0-dione is generally carried out in conventional manner such as, for example, oxidizing the 6 methyl 90c fluoro 115,17a dihydroxy 4 pregnene-3,20-dione in acetic acid solution with chromic anhydride using a calculated amount of chromic anhydride or a slight excess such as from ten to thirty percent excess above the calculated amount; or oxidizing the 6 methyl 9a fluoro 11,13,170: dihydroxy 4 pregnene-3,20-dione with a haloamide or haloimide of an acid such as N-bromoacetamide, N-chlorosuccinimide, N- bromosuccinimide in pyridine, dioxane, or other solvent solutions. After termination of the oxidation, the oxidant is generally destroyed such as by addition of methyl alcohol, ethyl alcohol, when chromic acid was used or an alkali bisulfite when either chromic acid or N-bromosuccinimide and other N-haloacylamides were used. Thereafter, the product 6-methyl-9a-fluoro-17a-hydroxy- 4-pregnene-3,l1,20-trione is obtained by conventional means such as extraction with water-immiscible solvents, for example, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, ether, benzene, toluene, or the like, or by chromatography, if deemed necessary.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

EXAMPLE 1 6a-methyl-9a-fluor0-1 119,1 7 a,21 -trihydr0xy-4-preg'nene- 3,20-di0ne 21 -methanesulf0nate A solution was prepared containing one gram of 6amethyl-9a-fluorohydrocortisone [George B. Spero et al.,

J. Am. Chem. Soc., 79, 1515 (1957)] in ten milliliters milliliters of sufiicient dilute (five percent) hydrochloric acid to neutralize the pyridine. The mixture was then filtered, the precipitate thus collected, washed with water, and dried to give 1.2 gram of crude 6ot-methyl-9u-fluoro- 11fl,17oc,21 trihydroxy 4 -'pregnene 3,20 dione 21 methanesulfonate of melting point 166 to 178 degrees centigrade (dec.).

EXAMPLE 2 6 a-methyl-9a-flu0ro-1 113,1 7a-dihydr0xy-21-iodo-4- pregnene-3,20-dione 750 milligrams of crude methanesulfonate of 6amethyl 9a fluoro 11,6,17a,21 trihydroxy- 4 pregnene-3,20-dione was dissolved in fifteen milliliters of acetone and treated with a solution of 750' milligrams of sodium iodide in fifteen milliliters of acetone. The 'mixture was heated under refiux with stirring for a period of fifteen minutes. The heating was then discontinued and the mixture concentrated to dryness at reduced pressure to give 6a-methyl-9a-fluoro-11p,17u-dihydroxy-21- iodo-4-pregnene-3,20-dione.

EXAMPL 3 6 a-methyZ-Qa-fluOrO-J 1 3,1 7a-dihydroxy-4-pregnene- 3 ,ZO-dione TABLE I Fraction: Solvent 1-15 Skellysolve B-hexane% acetone.

16 Acetone.

Fractions 5 through 16, inclusive, were combined and evaporated to give 455 milligrams (80.3%) of crystals. After two recrystallizations of the crystalline material from acetone-Skellysolve B hexanes, 0.36 gram of pure 6a. methyl 9a fluoro 115,170; dihydroxy 4 pregnene-3,20-dione was obtained having a melting point of 237 to 239 degrees centigrade and rotation [04 plus 103 degrees in acetone.

Analysis.Calcd. for C H O F C, 69.81; H, 8.26; F, 5.02. Found: C, 70.08; H, 8.66; F, 5.13.

EXAMPLE 4 6m-methyl-9a-flu'0r0-17a-hydr0xy-4-pregnerte-3,11,20- trione A mixture was prepared containing 0.3 gram of 60r methyl 9a fluoro 11,3,17a dihydroxy 4 pregnene 3,20-dione, 100 milligrams of chromic anhydride, ten milliliters of glacial acetic acid and one-half milliliter of EXAMPLE 5 In the same manner shown in Example 1, treating other 6u-alkyl-9a-fluorohydrocortisones and 6a-alkyl-9afiuorocortisones or the 6-aryl analogues thereof with the chlorides or bromides of toluenesulfonic acid, methanesulfonic acid and other organic sulfonic acids, give the corresponding 2l-toluene-sulfonate, the ZI-methanesulfonate, or the like, of the corresponding 6a-alkyl-9dfiuoro-hydrocortisone and 6u-alkyl-9a-fiuorocortisone or 6-aryl analogues thereof wherein the alkyl group is -methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,

hexyl, and the aryl group is phenyl, or the like.

Treating the thus obtained 21-toluenesulfonate, 21- methanesulfonate or other 21-alkylor 21-arylsulfonates of 6a-alkyl-9a-fiuorohydrocortisone and 6a-alkyl-9afluorocortisone or the 6a-aryl analogues thereof with sodium or potassium iodide in acetone at elevated terriperature, usually reflux temperature, yields the corresponding 21-iodo compound such as, for example, 6&- ethyl 9a fluoro 115,170: dihydroxy 21 iodo 4 pregnene-3,20-dione, 6zx-propyl-9a-flu0ro-11(3,17a-dihydroxy-21-iodo-4-pregnene-3,20-dione, 6a-isopropyl-9a-fluoro 115,170 dihydroxy 21 iodo 4 pregnene 3,20 dione. 6a-butyl-9a-fluoro-1 1,9,17a-dihydroxy-2l-iodo-4- pregnene-3,20-dione, 6u-isobutyl-9a-fluoro-1 1fi,17a-dihydroxy-21-iodo-4-pregnene-3,20-dione, 6a-pentyl-9a-fiuoro- 1 1,8,17a-dihydroxy-21-iodo-4-pregnene-3 ,20-dione, 6a.- phenyl 9a. fluoro 115,170; dihydroxy 21 iodo 4 pregnene-3,20-dione, 6m-methyl-9a-fluoro-17a-hydroxy-21- iodo-4-pregnene-3, l 1,20-trione, 6a-ethyl-9rx-fluoro- 1 7ahydroxy-2 1-iodo-4-pregnene-3,1 1,20-trione, 6a-propyl-9afluoro 17a hydroxy 21 iodo 4 pregnene 3,11,20 trione, 6oz isopropyl 9a fluoro 17a hydroxy 21 iodo-4-pregnene-3,1 1,20-trione, 6oc-bUtYI-9oc-flL1OIO-l7u-hY- droxy-21-iodo-4-pregnene3,11,20-trione, 6lZ-iSOb1lty1-9OL- fluoro 17a hydroxy 21 iodo 4 pregnene 3,11,20 trione, Ga-pentyl 9oz fluoro 17a hydroxy 21 iodo- 4 pregnene 3,11,20 trione, 6a hexyl 9a fluoro 17a hydroxy 21 iodo 4 pregnene 3,11,20 trione, 6a. phenyl c fluoro 17a hydroxy 21 iodo 4 pregnene-3,11,20-trione, and the like.

Treating the thus obtained 6a-alky1-9rx-fluoro-115,170:- dihydroxy-21-iodo-4-pregnene-3,20-diones and 6or-alkyl- 9a fluoro 170. hydroxy 21 iodo 4 pregnene 3,11,20-triones with a reducing agent, such as zinc in acetic acid, sodium bisulfite, sodium or potassium thiosulfate produces the corresponding 6a-alkyl-9a-fluoro- 1113,l7a-dihydroxy-4-pregnene-3,20-diones and 6a-alkyl- 9a-fluor-o-17a-hydroxy-4-pregnene-3, 1 1,20-triones wherein the alkyl groupis ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or aryl such as. phenyl, or the like.

Instead of the 6a-methyl-9a-fluoro-hydrocortisone or cortisone, the 6/3-epimer can be used in the above examples and if the reaction conditions are kept near neutral, the 6B-epimers, such as 6p-methyl-9ot-fluoro- 11,8,17u-dihydroxy-4-pregnene-3,20-dione and 6,8-methyl- 9a-fluoro-17a-hydroxy-4-prengene-3,11,20-trione can be isolated from the reaction mixture. The thus obtained 6,8-epimers yield the Gd-epimers by treatment of the 6B- epirner with acid or base in an organic solvent, e. g., ethanol at room temperature.

EXAMPLE 6 6 wmethyl-9a-fluor0-1 1 3,1 7a-dihydroxy-4- pregnene-3,20-dione A mixture of one gram of 6a-methyl-1lfl,17a-dihydroxy-4-pregnene-3,20-dione, 650 milligrams of N-bromo acetamide and six milliliters of pyridine were stirred in the dark for a period of thirty minutes. The mixture was cooled in an ice-water bath and a stream of sulfur dioxide was directed onto the surface of the stirred mixture until a negative potassium iodide-starch test was obtained. Fifty milliliters of water was then'added to the mixture and the mixture was maintained at about five degrees centigrade for thirty minutes. The precipitated white solid was filtered, washed with water, and dried under vacuum. After crystallization from acetone there was obtained about 0.75 gram of 6ot-methy1-17oc. hydroxy-4,9 1 1 -pregnadiene-3,20-dione.

0.5 gram of 6a-methy1-17a-hydroxy-4,9(11)-pregnainto water and extracted with methylene chloride.

hydroxy-4-pregnene-3, 1 1,20-triones ldiene-3,20-dione was dissolved in twenty milliliters of methylene chloride and thereto was added a solution of .0116 milliliter of 71 percent perchloric acid in tencmilli- .liters of water and 200 milligrams of N-bromoacetamide in fifty milliliters of tertiary butyl alcohol. The solution was maintained at room temperature for fifteen minutes and then mixed with a solution of 0.3 gram of sodium sulfite in twelve milliliters of water. The mix- The white crystalline precipitate was filtered,

17ocdihydroxy-.4- pregnene-3,20-dione, 0.45 gram of anhydrous potassium acetate and twenty milliliters of acetone was heated at its refluxing temperature for a period The mixture was then cooled and poured The methylene chloride extract was dried and poured over a column of 25 grams of Florisil synthetic magnesium silicate. The column was developed with Skellysolve B of five hours.

hexane hydrocarbons containing increasing portions of "acetone. eluate contained 6ot-methyl-9(11)-oxido-17a-hydroxy-4- pregnene-3,20-dione.

The Skellysolve B plus ten percent acetone A solution of one gram of 6a-methyl-9(1l)-oxido-17o- Ihydroxyl-pregnene-3,ZO-dione was dissolved in fifty milliliters of methylene chloride and thereto was added five milliliters of 48 percent hydrofluoric acid and 0.5 milli- :liter of 71 percent perchloric acid. The mixture was stirred vigorously for six hours and then poured into an excess of cold aqueous five percent sodium bicarbonate solution. The methylene chloride layer was separated,

dried with anhydrous sodium sulfate and then poured .over a column of 100 grams of Florisil synthetic magnesium silicate. solve B hexanes and acetone, the fractions containing ten The .column was developed with Skellypercent acetone were recrystallized from acetone and Skellysolve B hexanes to give pure 6u-methyl-9m-fiuoro- 115,17a-dihydroxy-4-pregnene 3,ZO-dione of melting point 237 to 239 degrees centigrade.

Followingthe procedure described in Example 6, but

substituting other 6a-alkyl-11,8,17u-dihydroxy-4-pregnene- 3,20-diones for the 6u.-methyl-11 3,17a-dihydroxy-4-pregnene-3,20-dione wherein the alkyl radical is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or an aryl, such as phenyl, or the like, results in the corresponding 60calkyl 9o; fluoro 11,8,1704 -,dihydroxy 4 pregnene- 3,20-dione vwherein the alkyl group will be ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl; or an aryl such as phenyl, or the like.

EXAMPLE 7 dione results in the corresponding 6a-alky1-9m-fluoro-17awherein the alkyl anol.

. 8 group is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or. aryl such as phenyl,. orthe like.

In the same manner as sho'wnwith the- 6ot-epimers the 6fi-epimers may be used as starting materials for the above Examples 6 and7.

EXAMPLE 8 6-methyl-9oz-flu0ro-11fi,17a-dihydr0xy 1,4 pregnadiene- 3,20-di0ne from 6ot-methyl-9auoro-Z 1 5,1 7 a-aihydroxy-4-pregnene-3,20-di0ne Six 100-milliliter portions of a medium in 250emilliliter Erlenmeyer flasks containing one percent glucose, two percent corn steep liquor (60 percent solids) and tap water was adjusted to a pH of 5.9. This medium was sterilized for minutes at fifteen pounds per square inch pressure and inoculated with a one to two day growth of Septomyxa affinis ATCC 6737. 'The Erlenmeyer flasks were shaken at room temperature at about 25 degrees centigrade for a period of three days. At the endof this period this 600-milliliter volume was used as an inoculum for ten liters of the same glucose-corn liquor medium which in additioncontained ten milliliters of an antifoam (a mixture of lard oil and octadecanol). The fermentor was placed into the water bath, adjusted to 28 degrees centigrade, and the contents stirred (300 R. P. M.) and aerated (0.5 l. air/l0 1. beer). After 17 hours of incubation, when a good growth developed and the acidity rose to pH 6.7, two grams of L-I1'lethyl-9OL- fiuoro-l1B,17 t-dihydroxy-4-pregnene-3,20-dione plus one gram of 3kfitObiSIlOf't4ChO1fiH2273.1, dissolved in 115 milliliters of dimethylformamide, was added and the incubation (conversion) carried out at the same temperature and aeration for 24 hours. The mycelium was filtered off and the steroidal material was extracted with methylene chloride, the methylene chloride. extracts evaporated to dryness, and the resulting residue chromatographed over a Florisil column. The column was packed with 200 grams of Florisil and was developed with five 400-milliliter fractions each of methylene chloride, Skellysolve B-acetone mixtures of- 9:1, 8:2, 7:3, 1:1, and meth- The fraction eluted with Skellysolve B-acetone (7:3) was evaporated andrecrystallizated from acetone to give 6u-methyl-9a-fluoro-11{3,17u-dihydroxy1,4-preg- ,nadiene-3,20-dione of melting point 292 to 303 degrees centigrade.

It is to be understood that the invention is not to be limited tothe exact details of operation or exact comfluoro 17cc hydroxy-4-pregnene- 3,11,20-trione.

References Cited in the file of this patent UNITED STATES PATENTS Fried Sept. 18, 1956 OTHER REFERENCES Spero et al.: J. A. C. S., 78, December 5, 1956, pages 6213, 6214. I 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 6-METHYL - 9A - FLUORO - 11B,17A - DIHYDROXY - 4 - PREGNENE3,20-DIONE AND 6-METHYL-9A-FLUORO-17A-HYDROXY-4-PREGNENE-3,11,20-TRIONE. 